11,12-Oxidoarachidonic acid derivatives and methods of their use in treating dry eye disorders

ABSTRACT

11,12-Oxidoarachidonic acid derivatives and methods of their use for treating dry eye are disclosed.

This application claims priority to U.S. Provisional Application, SerialNo. 60/304,988, filed Jul. 12, 2001.

[0001] The present invention is directed to the treatment of dry eyedisorders. In particular, the present invention is directed towardcertain novel 11,12-oxidoarachidonic acid derivatives and their use inthe treatment of dry eye.

BACKGROUND OF THE INVENTION

[0002] Dry eye, also known generically as keratoconjunctivitis sicca, isa common ophthalmological disorder affecting millions of Americans eachyear. The condition is particularly widespread among post-menopausalwomen due to hormonal changes following the cessation of fertility. Dryeye may afflict an individual with varying severity. In mild cases, apatient may experience burning, a feeling of dryness, and persistentirritation such as is often caused by small bodies lodging between theeye lid and the eye surface. In severe cases, vision may besubstantially impaired. Other diseases, such as Sjogren's disease andcicatricialpemphigoid manifest dry eye complications.

[0003] Although it appears that dry eye may result from a number ofunrelated pathogenic causes, all presentations of the complication sharea common effect, that is the breakdown of the pre-ocular tear film,which results in dehydration of the exposed outer surface and many ofthe symptoms outlined above (Lemp, Report of the National EyeInstitute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAOJournal, volume 21, number 4, pages 221-231 (1995)).

[0004] Practitioners have taken several approaches to the treatment ofdry eye. One common approach has been to supplement and stabilize theocular tear film using so-called artificial tears instilled throughoutthe day. Other approaches include the use of ocular inserts that providea tear substitute or stimulation of endogenous tear production.

[0005] Examples of the tear substitution approach include the use ofbuffered, isotonic saline solutions, aqueous solutions containing watersoluble polymers that render the solutions more viscous and thus lesseasily shed by the eye. Tear reconstitution is also attempted byproviding one or more components of the tear film such as phospholipidsand oils. Phospholipid compositions have been shown to be useful intreating dry eye; see, e.g., McCulley and Shine, Tear film structure anddry eye, Contactologia, volume 20(4), pages 145-49 (1998); and Shine andMcCulley, Keratoconjunctivitis sicca associated with meibomian secretionpolar lipid abnormality, Archives of Ophthalmolog, volume 116(7), pages849-52 (1998). Examples of phospholipid compositions for the treatmentof dry eye are disclosed in U.S. Pat. No. 4,131,651 (Shah et al.), U.S.Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S.Pat. Nos. 4,744,980 and 4,883,658 (Holly), U.S. Pat. No. 4,914,088(Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No.5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.),5,371,108 (Korb et al.) and U.S. Pat. No. 5,578,586 (Glonek et al.).U.S. Pat. No. 5,174,988 (Mautone et al.) discloses phospholipid drugdelivery systems involving phospholipids, propellants and an activesubstance.

[0006] U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of ocularinserts in the treatment of dry eye. Other semi-solid therapy hasincluded the administration of carrageenans (U.S. Pat. No. 5,403,841,Lang) which gel upon contact with naturally occurring tear film.

[0007] Another approach involves the provision of lubricating substancesin lieu of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo)discloses the use of a lubricating, liposome-based composition, and U.S.Pat. No. 5,800,807 (Hu et al.) discloses compositions containingglycerin and propylene glycol for treating dry eye.

[0008] Aside from the above efforts, which are directed primarily to thealleviation of symptoms associated with dry eye, methods andcompositions directed to treatment of the dry eye condition have alsobeen pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) disclosesthe use of sex steroids, such as conjugated estrogens, to treat dry eyecondition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen)discloses the use of finely divided calcium ion compositions tostimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773(Gressel et al.) discloses the use of microfine particles of one or moreretinoids for ocular tissue normalization.

[0009] Although these approaches have met with some success, problems inthe treatment of dry eye nevertheless remain. The use of tearsubstitutes, while temporarily effective, generally requires repeatedapplication over the course of a patient's waking hours. It is notuncommon for a patient to have to apply artificial tear solution ten totwenty times over the course of the day. Such an undertaking is not onlycumbersome and time consuming, but is also potentially very expensive.Transient symptoms of dry eye associated with refractive surgery havebeen reported to last in some cases from six weeks to six months or morefollowing surgery.

[0010] The use of ocular inserts is also problematic. Aside from cost,they are often unwieldy and uncomfortable. Further, as foreign bodiesintroduced in the eye, they can be a source of contamination leading toinfections. In situations where the insert does not itself produce anddeliver a tear film, artificial tears must still be delivered on aregular and frequent basis.

[0011] U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositionscontaining naturally occurring HETEs, or derivatives thereof, and theiruse in methods for treating dry eye. The compositions comprising HETEsincrease ocular mucin secretion.

[0012] Recent studies have also claimed that known anti-inflammatoryagents, such as methylprednisolone, provide relief of symptomsassociated with dry eye. See, for example, Marsh, et al., Topicalnonpreserved methylprednisolone therapy for keratoconjunctivitis siccain Sjogren syndrome, Ophthalmology, Volume 106 (4), pages 811-816(1999); and U.S. Pat. No. 6,153,607 (Pflugfelder et al.).

SUMMARY OF THE INVENTION

[0013] The present invention is directed to compounds, compositions andmethods of use. The present invention is particularly directed tocompositions and methods for the treatment of dry eye and otherdisorders requiring the wetting of the eye, including symptoms of dryeye associated with refractive surgery such as LASIK surgery. Morespecifically, the present invention discloses ophthalmic compositionscontaining 11,12-oxidoarachidonic acid derivatives, and methods usingthe same for treating dry eye type disorders. The compositions arepreferably administered topically to the eye.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The 11,12-oxidoarachidonic acid derivatives of the presentinvention are those of formula (I):

[0015] wherein:

[0016] R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, wherein:

[0017] R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

[0018] NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

[0019] OR⁴ comprises a free or functionally modified hydroxy group,e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

[0020] Hal is F, Cl, Br, or l;

[0021] SR²⁰ comprises a free or functionally modified thiol group; and

[0022] R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

[0023] A, B and D are the same or different and are C₁-C₅ alkyl, C₂-C₅alkenyl, C₂-C₅ alkynyl, or a C₃-C₅ allenyl group;

[0024] C is an oxirane or cyclopropane;

[0025] X is (CH₂)_(m) or (CH₂)_(m)O, wherein m is 1-6; and

[0026] Y is a phenyl ring optionally substituted with alkyl, halo,trihalomethyl, acyl, or a free or functionally modified hydroxy, amino,or thiol group; or

[0027] X—Y is (CH₂)_(p)Y¹; wherein p is 0-6; and

[0028] wherein:

[0029]  W is CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁸; wherein q is 0-2, and R⁸ is H, alkyl, or acyl;

[0030]  Z is H, alkyl, acyl, halo, trihalomethyl, or a free orfunctionally modified amino, thiol, or hydroxy group; and

[0031] is a single or double bond; or

[0032] X—Y is cyclohexyl or n-C₅H₁₁.

[0033] All of the compounds of the present invention are believed to benovel with the exception of compound 1 which is a naturally occurringsubstance that is commercially available from Cayman Chemical Co., AnnArbor, Mich., or can be synthesized by the method of Corey et. al.(Corey et. al., Org. Lett., 2:3437-3438 (2000)):

[0034] Included within the scope of the present invention are theindividual enantiomers of the compounds of the present invention, aswell as their racemic and non-racemic mixtures. The individualenantiomers can be enantioselectively synthesized from the appropriateenantiomerically pure or enriched starting material by means such asthose described below. Alternatively, they may be enantioselectivelysynthesized from racemic/non-racemic or achiral starting materials.(Asymmetric Synthesis; J. D. Morrison and J. W. Scott, Eds.; AcademicPress Publishers: New York, 1983-1985, volumes 1-5; Principles ofAsymmetric Synthesis; R. E. Gawley and J. Aube, Eds.; ElsevierPublishers: Amsterdam, 1996). They may also be isolated from racemic andnon-racemic mixtures by a number of known methods, e.g. by purificationof a sample by chiral HPLC (A Practical Guide to Chiral Separations byHPLC; G. Subramanian, Ed.; VCH Publishers: New York, 1994; ChiralSeparations by HPLC; A. M. Krstulovic, Ed.; Ellis Horwood Ltd.Publishers, 1989), or by enantioselective hydrolysis of a carboxylicacid ester sample by an enzyme (Ohno, M.; Otsuka, M. Organic Reactions,volume 37, page 1 (1989)). Those skilled in the art will appreciate thatracemic and non-racemic mixtures may be obtained by several means,including without limitation, nonenantioselective synthesis, partialresolution, or even mixing samples having different enantiomeric ratios.Departures may be made from such details within the scope of theaccompanying claims without departing from the principles of theinvention and without sacrificing its advantages. Also included withinthe scope of the present invention are the individual isomerssubstantially free of their respective enantiomers.

[0035] As used herein, the terms “pharmaceutically acceptable salt”,“pharmaceutically acceptable ester” and pharmaceutically acceptablethioester” means any salt, ester or thioester, respectively, that wouldbe suitable for therapeutic administration to a patient by anyconventional means without significant deleterious health consequences;and “ophthalmically acceptable salt”, “ophthalmically acceptable ester”and “ophthalmically acceptable thioester” means any pharmaceuticallyacceptable salt, ester or thioester, respectively, that would besuitable for ophthalmic application, i.e. non-toxic and non-irritating.

[0036] The term “free hydroxy group” means an OH. The term “functionallymodified hydroxy group” means an OH which has been functionalized toform: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; an ester, in which an acyl group issubstituted for the hydrogen; a carbamate, in which an aminocarbonylgroup is substituted for the hydrogen; or a carbonate, in which anaryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, oralkynyloxy-carbonyl group is substituted for the hydrogen. Preferredmoieties include OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,and OC(O)C₂H₅.

[0037] The term “free amino group” means an NH₂. The term “functionallymodified amino group” means an NH₂ which has been functionalized toform: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-,alkynyl-, or hydroxy-amino group, wherein the appropriate group issubstituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-,cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-,heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriategroup is substituted for one or both of the hydrogens; an amide, inwhich an acyl group is substituted for one of the hydrogens; acarbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, oralkynyl-carbonyl group is substituted for one of the hydrogens; or aurea, in which an aminocarbonyl group is substituted for one of thehydrogens. Combinations of these substitution patterns, for example anNH₂ in which one of the hydrogens is replaced by an alkyl group and theother hydrogen is replaced by an alkoxycarbonyl group, also fall underthe definition of a functionally modified amino group and are includedwithin the scope of the present invention. Preferred moieties includeNH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃, NHOH, and NH(OCH₃).

[0038] The term “free thiol group” means an SH. The term “functionallymodified thiol group” means an SH which has been functionalized to form:a thioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; or a thioester, in which an acyl groupis substituted for the hydrogen. Preferred moieties include SH,SC(O)CH₃, SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃.

[0039] The term “acyl” represents a group that is linked by a carbonatom that has a double bond to an oxygen atom and a single bond toanother carbon atom.

[0040] The term “alkyl” includes straight or branched chain aliphatichydrocarbon groups that are saturated and have 1 to 6 carbon atoms. Thealkyl groups may be interrupted by one or more heteroatoms, such asoxygen, nitrogen, or sulfur, and may be substituted with other groups,such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy.Preferred straight or branched alkyl groups include methyl, ethyl,propyl, isopropyl, butyl and t-butyl.

[0041] The term “cycloalkyl” includes straight or branched chain,saturated or unsaturated aliphatic hydrocarbon groups which connect toform one or more rings, which can be fused or isolated. The rings may besubstituted with other groups, such as halogen, hydroxyl, aryl, aryloxy,alkoxy, or alkyl. Preferred cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

[0042] The term “heterocycloalkyl” refers to cycloalkyl rings thatcontain at least one heteroatom such as O, S, or N in the ring, and canbe fused or isolated. The rings may be substituted with other groups,such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or alkyl. Preferredheterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl,piperazinyl, and tetrahydropyranyl.

[0043] The term “alkenyl” includes straight or branched chainhydrocarbon groups having 1 to 6 carbon atoms with at least onecarbon-carbon double bond, the chain being optionally interrupted by oneor more heteroatoms. The chain hydrogens may be substituted with othergroups, such as halogen. Preferred straight or branched alkenyl groupsinclude allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

[0044] The term “cycloalkenyl” includes straight or branched chain,saturated or unsaturated aliphatic hydrocarbon groups which connect toform one or more non-aromatic rings containing a carbon-carbon doublebond, which can be fused or isolated. The rings may be substituted withother groups, such as halogen, hydroxyl, alkoxy, or alkyl. Preferredcycloalkenyl groups include cyclopentenyl and cyclohexenyl.

[0045] The term “heterocycloalkenyl” refers to cycloalkenyl rings whichcontain one or more heteroatoms such as O, N, or S in the ring, and canbe fused or isolated. The rings may be substituted with other groups,such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or alkyl. Preferredheterocycloalkenyl groups include pyrrolidinyl, dihydropyranyl, anddihydrofuranyl.

[0046] The term “carbonyl group” represents a carbon atom double bondedto an oxygen atom, wherein the carbon atom has two free valencies.

[0047] The term “aminocarbonyl” represents a free or functionallymodified amino group bonded from its nitrogen atom to the carbon atom ofa carbonyl group, the carbonyl group itself being bonded to another atomthrough its carbon atom.

[0048] The term “halogen” represents fluoro, chloro, bromo, or iodo.

[0049] The term “aryl” refers to carbon-based rings which are aromatic.The rings may be isolated, such as phenyl, or fused, such as naphthyl.The ring hydrogens may be substituted with other groups, such as alkyl,halogen, free or functionalized hydroxy, trihalomethyl, etc. Preferredaryl groups include phenyl, 3-(trifluoromethyl)phenyl, 3-chlorophenyl,and 4-fluorophenyl.

[0050] The term “heteroaryl” refers to aromatic hydrocarbon rings whichcontain at least one heteroatom such as O, S, or N in the ring.Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with openvalency may be substituted with other groups, such as alkyl or halogen.Examples of heteroaryl groups include imidazole, pyridine, indole,quinoline, furan, thiophene, pyrrole, tetrahydroquinoline,dihydrobenzofuran, and dihydrobenzindole.

[0051] The terms “aryloxy”, “heteroaryloxy”, “alkoxy”, “cycloalkoxy”,“heterocycloalkoxy”, “alkenyloxy”, “cycloalkenyloxy”,“heterocycloalkenyloxy”, and “alkynyloxy” represent an aryl, heteroaryl,alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,heterocycloalkenyl, or alkynyl group, respectively, attached through anoxygen linkage.

[0052] The terms “alkoxycarbonyl”, “aryloxycarbonyl”,“heteroaryloxycarbonyl”, “cycloal koxycarbonyl”, “heterocycloalkoxycarbonyl”, “alkenyloxycarbonyl”, “cycloalkenyloxycarbonyl”,“heterocycloalkenyloxycarbonyl”, and “alkynyloxycarbonyl” represent analkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy,alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or alkynyloxy group,respectively, bonded from its oxygen atom to the carbon of a carbonylgroup, the carbonyl group itself being bonded to another atom throughits carbon atom.

[0053] Preferred compounds of the present invention include those offormula I, wherein:

[0054] R¹ is CO₂R, wherein R is H or CO₂R forms a pharmaceuticallyacceptable salt or a pharmaceutically acceptable ester;

[0055] A and B are C₁₋₅ alkyl, alkenyl, or alkynyl or C₃₋₅ allenylgroup;

[0056] C is

[0057] D is a C₃ alkyl, alkenyl, or alkynyl group;

[0058] X is (CH₂)_(m) or (CH₂)_(m)O, wherein m is 1 or 2; and

[0059] Y is a phenyl ring optionally substituted with halo,trihalomethyl, or a free or functionally modified hydroxy group; or

[0060] X—Y is n-C₅H₁₁ or cyclohexyl; or

[0061] X—Y is Y¹; wherein

[0062] Among the particularly preferred compounds of formula I arecompounds 1-4.

[0063] Compounds 2-4 can be synthesized as detailed in the followingexamples 1-3:

Example 1

[0064]

10-[(1R,2S)-2-(5-Phenyl-pent-2-en-1 -yl)-oxiran-1 -yl]-deca-5,8-dienoicacid (2):

[0065] Reaction of 4-phenyl-1-butyne (5; commercially available fromLancaster Synthesis, Windham, N.H.) with allyl bromide underphase-transfer conditions (CH₂Cl₂, n-BU₄NCl, water, KOH), selectiveoxidation of the alkene moiety using catalytic OsO₄/pyr andstoichiometric N-methylmorpholine-N-oxide, and oxidative cleavage of theresultant diol using NalO₄ affords 6-phenyl-hex-3-ynal (6). Lithiationof phosphine oxide 7 [Katritzky, Alan R., Feng, Daming, Lang, HengyuanJ. Org. Chem., volume 62(12) page 4131 (1997)], Wittig condensation with6, and heating of the intermediate dienyne (not shown) withp-toluenesulfonic acid in ethanol affords enyne 8. Asymmetricdihydroxylation of 8 with AD mix α (Aldrich Chemical Co., Milwaukee) andmethanesulfonamide [Sharpless, K. B., Amberg, W., Bennani, Y. Crispino,G. A.; Hartung, J; Jeong, K. S.; Kwong, H.-L.; Morikawa, K.; Wang,Z.-M.; Xu, D. Zhang, X.-L. J. Org. Chem., volume 57, page 2768 (1992)],followed by selective reduction with H₂ over Pd/BaSO₄, affords β-hydroxylactone 9. Sequential treatment of 9 with CH₃SO₂Cl/NEt₃ anddiisobutylaluminum hydride (DIBAL-H) provides lactol 10. Sodiumborohydride reduction, K₂CO₃ treatment, and oxidation of the resultingβ-hydroxyepoxide with the Dess-Martin reagent produces the epoxyaldehyde11. Wittig olefination of 11 and known ylide 12 [Zamboni, R.; Milettee,S.; Rokach, J. Tetrahedron Lett., volume 24, page 4899 (1983)] followedby saponification of the resulting methyl ester with LiOH indimethoxyethane (DME)/water yields 2.

Example 2

[0066]

Synthesis of10-[(1R,2S)-2-(3-Cyclohexylprop-2-enyl)-oxiran-1-yl]-deca-5,8-dienoicacid (3):

[0067] Allylation of cyclohexylacetylene (13; commercially availablefrom Chemsampco Inc., Trenton, N.J., or preparable by the method of Wangand Fortunak, PCT Intl. Appl. WO 0018706 A1) with allyl bromide underphase-transfer conditions (CH₂Cl₂/water, KOH, allyl bromide, n-BU₄NCl)affords 4-cyclohexylbut-3ynal (14), which is condensed with phosphineoxide 7 in the presence of n-BuLi to afford an intermediate dienyne (notshown). Heating the dienyne with p-toluenesulfonic acid in ethanolaffords the desired enyne 15. Asymmetric dihydroxylation of 15 using ADmix α in the presence of CH₃SO₂NH₂ provides β-hydroxy lactone 16, whichis sequentially reduced with H₂ over Pd/BaSO₄, treated with MsCl/NEt₃,and reduced with DIBAL-H to yield mesylate 17. Sodium borohydridereduction, K₂CO₃ treatment, and oxidation with the Dess-Martin reagentproduces the epoxyaldehyde 18. Wittig olefination of 18 with ylide 12followed by saponification with LiOH in DME/water affords 3.

Example 3

[0068]

Synthesis of10-[3-(3-Trifluoromethyl-phenoxymethyl)-oxiranyl]-deca-5,8-dienoic acidisopropyl ester (4)

[0069] Treatment of epoxide 21 [Gao, L.-X.; Murai, A. Heterocycles,volume 42(2), page 745 (1996)] sequentially with CH₃SO₂Cl/NEt₃, KCN indimethylformamide, K₂CO₃ in methanol, and DIBAL-H affords aldehyde 20.Modified Horner-Emmons condensation of the aldehyde with(CF₃CH₂O)₂P(O)CH₂CO₂Me in the presence of KN(SiMe₃)₂ and 18-crown-6 inTHF at −78° C. affords cis-enoate 21. Reduction of 21 with DIBAL-Hprovides allyl alcohol 22, which is treated sequentially withp-toluenesulfonyl chloride/pyridine, KBr in dimethylformamide, and3-trifluoromethylphenol/K₂CO₃ in acetone to give ether 23. Desilylationof 23 with tetra-n-butylammonium fluoride, followed by oxidation of theproduct alcohol with the Dess-Martin reagent, affords aldehyde 24.Wittig condensation of 24 with ylide 12 yields triene ester 25, which issaponified with LiOH in DME/water to afford 4.

[0070] Salt forms of the formula I compounds are preferred as it isbelieved that the neat salts are more stable than the corresponding neatacids. Preferred salts of the present invention are those wherein aterminal carboxylate of formula I (i.e., wherein R¹ is CO₂R) forms asalt with cations selected from: Na⁺, K⁺, NH₄ ⁺, benzyltrimethylammoniumion, tetrabutylammonium ion, and phenyltrimethyl ammonium ion.

[0071] The compositions of the present invention comprise one or morecompounds of formula I and a pharmaceutically acceptable carrier. Thecompositions are formulated in accordance with methods known in the artfor the particular route of administration desired for the prevention,treatment or amelioration of the particular disease or disordertargeted. As used herein, the term “pharmaceutically acceptable carrier”refers to any formulation which is safe, and provides the appropriatedelivery of an effective amount of one or more compounds of formula Ifor the prevention, treatment or amelioration of the disease or disordertargeted.

[0072] The compositions of the present invention comprise apharmaceutically effective amount of one or more compounds of formula I.As used herein, a “pharmaceutically effective amount” is one which issufficient to reduce or eliminate signs or symptoms of dry eye or otherdisorders requiring the wetting of the eye. Generally, the compounds offormula I will be contained in a composition of the present invention ina concentration range of about 0.00001 to 10 percent weight/volume (“%w/v”). Preferred topically administrable ophthalmic compositions willcontain one or more compounds of formula I in a concentration of fromabout 0.00001-0.01% w/v.

[0073] The present invention is particularly directed to compositionsuseful in treating dry eye. Preferably, such compositions will beformulated as solutions, suspensions and other dosage forms for topicaladministration. Aqueous solutions are generally preferred, based on easeof formulation, biological compatibility (especially in view of themalady to be treated, e.g., dry eye-type diseases and disorders), aswell as a patient's ability to easily administer such compositions bymeans of instilling one to two drops of the solutions in the affectedeyes. However, the compositions may also be suspensions, viscous orsemi-viscous gels, or other types of solid or semi-solid compositions.Suspensions may be preferred for compounds of formula (I) which aresparingly soluble in water.

[0074] Preferably, the compositions of the present invention will alsocontain a surfactant. Various surfactants useful in topical ophthalmicformulations may be employed. The surfactant(s) may provide additionalchemical stabilization of the formula I compounds and may furtherprovide for the physical stability of the compounds. In other words, thesurfactants may aid in preventing chemical degradation of the compoundsof formula I and also prevent the compounds from binding to thecontainers in which their compositions are packaged. As used herein, “aneffective concentration of surfactant(s)” refers to a concentration thatenhances the chemical and physical stability of formula I compound(s).Examples of surfactants include, but are not limited to: Cremophore® EL,polyoxyl 20 ceto stearyl ether, polyoxyl 40 hydrogenated castor oil,polyoxyl 23 lauryl ether and poloxamer 407 may be used in thecompositions. A preferred surfactant is polyoxyl 40 stearate. Theconcentration of surfactant will vary, depending on the concentration offormula I compound(s) and optional ethanol present in the formulation.In general, however, the surfactant(s) concentration will be about 0.001to 2.0% w/v. Preferred compositions of the present invention willcontain about 0.1% w/v of polyoxyl 40 stearate.

[0075] The compositions of the present invention may also includevarious other ingredients, such as tonicity agents, buffers,preservatives, co-solvents and viscosity building agents.

[0076] Various tonicity agents may be employed to adjust the tonicity ofthe composition, preferably to that of natural tears for ophthalmiccompositions. For example, sodium chloride, potassium chloride,magnesium chloride, calcium chloride, dextrose and/or mannitol may beadded to the composition to approximate physiological tonicity. Such anamount of tonicity agent will vary, depending on the particular agent tobe added. In general, however, the compositions will have a tonicityagent concentration of about 0.1-1.5% w/v. Sodium chloride in the amountof 0.75% w/v is preferred.

[0077] An appropriate buffer system (e.g., sodium phosphate, sodiumacetate, sodium citrate, sodium borate or boric acid) may be added tothe compositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed. Ingeneral, however, such a concentration will range from about 0.02 to2.0% w/v.

[0078] Antioxidants may be added to compositions of the presentinvention to protect the formula I compounds from oxidation duringstorage. Examples of such antioxidants include, but are not limited to,vitamin E and analogs thereof, ascorbic acid and derivatives, andbutylated hydroxyanisole (BHA).

[0079] Compositions formulated for the treatment of dry eye-typediseases and disorders may also comprise aqueous carriers designed toprovide immediate, short-term relief of dry eye-type conditions. Suchcarriers can be formulated as a phospholipid carrier or an artificialtears carrier, or mixtures of both. As used herein, “phospholipidcarrier” and “artificial tears carrier” refer to aqueous compositionswhich: (i) comprise one or more phospholipids (in the case ofphospholipid carriers) or other compounds, which lubricate, “wet,”approximate the consistency of endogenous tears, aid in natural tearbuild-up, or otherwise provide temporary relief of dry eye symptoms andconditions upon ocular administration; (ii) are safe; and (iii) providethe appropriate delivery vehicle for the topical administration of aneffective amount of one or more compounds of formula I. Examples orartificial tears compositions useful as artificial tears carriersinclude, but are not limited to, commercial products, such as TearsNaturale®, Tears Naturale II®, Tears Naturale Free®, and Bion Tears®(Alcon Laboratories, Inc., Fort Worth, Tex.). Examples of phospholipidcarrier formulations include those disclosed in U.S. Pat. No. 4,804,539(Guo et al.), U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088(Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No.5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S.Pat. No. 5,371,108 (Korb et al.), U.S. Pat. No. 5,578,586 (Glonek etal.); the foregoing patents are incorporated herein by reference to theextent they disclose phospholipid compositions useful as phospholipidcarriers of the present invention.

[0080] Other compounds designed to lubricate, “wet,” approximate theconsistency of endogenous tears, aid in natural tear build-up, orotherwise provide temporary relief of dry eye symptoms and conditionsupon ocular administration the eye are known in the art. Such compoundsmay enhance the viscosity of the composition, and include, but are notlimited to: monomeric polyols, such as, glycerol, propylene glycol,ethylene glycol; polymeric polyols, such as, polyethylene glycol,hydroxypropylmethyl cellulose (“HPMC” ), carboxy methylcellulose sodium,hydroxy propylcellulose (“HPC” ), dextrans, such as, dextran 70; watersoluble proteins, such as gelatin; and vinyl polymers, such as,polyvinyl alcohol, polyvinylpyrrolidone, povidone and carbomers, suchas, carbomer 934P, carbomer 941, carbomer 940, carbomer 974P.

[0081] Other compounds may also be added to the ophthalmic compositionsof the present invention to increase the viscosity of the carrier.Examples of viscosity enhancing agents include, but are not limited to:polysaccharides, such as hyaluronic acid and its salts, chondroitinsulfate and its salts, dextrans, various polymers of the cellulosefamily; vinyl polymers; and acrylic acid polymers. In general, thephospholipid carrier or artificial tears carrier compositions willexhibit a viscosity of 1 to 400 centipoises (“cps”). Preferredcompositions containing artificial tears or phospholipid carriers willexhibit a viscosity of about 25 cps.

[0082] Topical ophthalmic products are typically packaged in multidoseform. Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben,phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, orother agents known to those skilled in the art. Such preservatives aretypically employed at a level of from 0.001 to 1.0% w/v. Unit dosecompositions of the present invention will be sterile, but typicallyunpreserved. Such compositions, therefore, generally will not containpreservatives.

[0083] The preferred compositions of the present invention are intendedfor administration to a human patient suffering from dry eye or symptomsof dry eye. Preferably, such compositions will be administeredtopically. In general, the doses used for the above described purposeswill vary, but will be in an effective amount to increase mucinproduction in the eye and thus eliminate or improve dry eye conditions.Generally, 1-2 drops of such compositions will be administered 1-10times per day for the treatment of dry eye or other ocular disease ordisorder. Preferably, 1-2 drops of the compositions will be administered1-4 times per day.

[0084] A representative eye drop formulation is provided in Example 4below.

Example 4

[0085] Ingredient Amount (% w/v) Compound of formula I 0.00001-0.01Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium Chloride 0.75 DisodiumEdetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH = 7.5 PurifiedWater q.s. 100%

[0086] The above composition is prepared by the following method. Thebatch quantities of boric acid, sodium chloride, disodium edetate, andpolyquaternium-1 are weighed and dissolved by stirring in 90% of thebatch quantity of purified water. The pH is adjusted to 7.5±0.1 withNaOH and/or HCl. Under yellow light or reduced lighting, the batchquantity of the compound of formula I as a stock solution is measuredand added. Purified water is added to q.s. to 100%. The mixture isstirred for five minutes to homogenize and then filtered through asterilizing filter membrane into a sterile recipient.

[0087] This invention has been described by reference to certainpreferred embodiments; however, it should be understood that it may beembodied in other specific forms or variations thereof without departingfrom its special or essential characteristics. The embodiments describedabove are therefore considered to be illustrative in all respects andnot restrictive, the scope of the invention being indicated by theappended claims rather than by the foregoing description.

What is claimed is:
 1. A composition for the treatment of dry eye andother disorders requiring the wefting of the eye comprising apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of one or more compounds of the following formula I:

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂R formsa pharmaceutically acceptable salt or a pharmaceutically acceptableester; NR²R³and NR⁵R⁶are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ comprises a free orfunctionally modified hydroxy group, e.g., R⁴ is H, acyl; alkyl,cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br, or I; SR²⁰ comprises afree or functionally modified thiol group; and R²¹ is H or COSR²¹ formsa pharmaceutically acceptable salt or a pharmaceutically acceptablethioester; A, B and D are the same or different and are C₁-C₅ alkyl,C₂-C₅ alkenyl, C₂-C₅ alkynyl, or a C₃-C₅ allenyl group; C is an oxiraneor cyclopropane; X is (CH₂)_(m) or (CH₂)_(m)O, wherein m is 1-6; and Yis a phenyl ring optionally substituted with alkyl, halo, trihalomethyl,acyl, or a free or functionally modified hydroxy, amino, or thiol group;or X—Y is (CH₂)_(p)Y¹; wherein p is 0-6; and

wherein:  W is CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁸; wherein q is 0-2, and R⁸ is H, alkyl, or acyl;  Z is H,alkyl, acyl, halo, trihalomethyl, or a free or functionally modifiedamino, thiol, or hydroxy group; and

is a single or double bond; or X—Y is cyclohexyl or n-C₅H₁₁.
 2. Thecomposition of claim 1, wherein for the compound of formula I: R¹ isCO₂R, wherein R is H or CO₂R forms a pharmaceutically acceptable salt ora pharmaceutically acceptable ester; A and B are C₁₋₅ alkyl, alkenyl, oralkynyl or C₃₋₅ allenyl group; C is

D is a C₃ alkyl, alkenyl, or alkynyl group; X is (CH₂)_(m) or(CH₂)_(m)O, wherein m is 1 or 2; and Y is a phenyl ring optionallysubstituted with halo, trihalomethyl, or a free or functionally modifiedhydroxy group; or X—Y is n-C₅H₁₁ or cyclohexyl; or X—Y is Y¹; wherein


3. The composition of claim 2, wherein the compound of formula I isselected from the group consisting of:


4. The composition of claim 1, wherein the composition is a topicalophthalmic formulation.
 5. A method for the treatment of dry eye andother disorders requiring the wetting of the eye which comprisesadministering to a mammal a composition comprising a pharmaceuticallyacceptable carrier and a pharmaceutically effective amount of one ormore compounds of the following formula I:

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂R formsa pharmaceutically acceptable salt or a pharmaceutically acceptableester; NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ comprises a free orfunctionally modified hydroxy group, e.g., R⁴ is H, acyl; alkyl,cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br, or I; SR²⁰ comprises afree or functionally modified thiol group; and R²¹ is H or COSR²¹ formsa pharmaceutically acceptable salt or a pharmaceutically acceptablethioester; A, B and D are the same or different and are C₁-C₅ alkyl,C₂-C₅ alkenyl, C₂-C₅ alkynyl, or a C₃-C₅ allenyl group; C an oxirane orcyclopropane; X is (CH₂)_(m) or (CH₂)_(m)O, wherein m is 1-6; and Y is aphenyl ring optionally substituted with alkyl, halo, trihalomethyl,acyl, or a free or functionally modified hydroxy, amino, or thiol group;or X—Y is (CH₂)_(p)Y¹; wherein p is 0-6; and

wherein:  W is CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)q,CH═N, or CH₂NR⁸; wherein q is 0-2, and R⁸ is H, alkyl, or acyl;  Z is H,alkyl, acyl, halo, trihalomethyl, or a free or functionally modifiedamino, thiol, or hydroxy group; and

is a single or double bond; or X—Y is cyclohexyl or n-C₅H₁₁.
 6. Themethod of claim 5, wherein for the compound of formula I: R¹ is CO₂R,wherein R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester; A and B are C₁₋₅ alkyl, alkenyl, oralkynyl or C₃₋₅ allenyl group; C is

D is a C₃ alkyl, alkenyl, or alkynyl group; X is (CH₂)_(m) or(CH₂)_(m)O, wherein m is 1 or 2; and Y is a phenyl ring optionallysubstituted with halo, trihalomethyl, or a free or functionally modifiedhydroxy group; or X—Y is n-C₅H₁₁ or cyclohexyl; or X—Y is Y¹; wherein


7. The method of claim 6, wherein the compound of formula I is selectedfrom the group consisting of:


8. The method of claim 5, wherein the composition is a topicalophthalmic formulation.
 9. The method of claim 5 wherein the dry eye andother disorders requiring the wetting of the eye is symptoms of dry eyeassociated with refractive surgery.
 10. A compound of the followingformula I:

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ , or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂Rforms a pharmaceutically acceptable salt or a pharmaceuticallyacceptable ester; NR²R³ and NR⁵R⁶ are the same or different and comprisea free or functionally modified amino group, e.g., R², R³, R⁵ and R⁶ arethe same or different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH,or alkoxy, with the proviso that at most only one of R² and R³ are OH oralkoxy and at most only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ comprisesa free or functionally modified hydroxy group, e.g., R⁴ is H, acyl;alkyl, cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br, or I; SR²⁰comprises a free or functionally modified thiol group; and R²¹ is H orCOSR²¹ forms a pharmaceutically acceptable salt or a pharmaceuticallyacceptable thioester; A, B and D are the same or different and are C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, or a C₃-C₅ allenyl group; C is anoxirane or cyclopropane; X is (CH₂)_(m) or (CH₂)_(m)O, wherein m is 1-6;and Y is a phenyl ring optionally substituted with alkyl, halo,trihalomethyl, acyl, or a free or functionally modified hydroxy, amino,or thiol group; or X—Y is (CH₂)_(p)Y¹; wherein p is 0-6; and

wherein:  W is CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁸; wherein q is 0-2, and R⁸ is H, alkyl, or acyl;  Z is H,alkyl, acyl, halo, trihalomethyl, or a free or functionally modifiedamino, thiol, or hydroxy group; and

is a single or double bond; or X—Y is cyclohexyl or n-C₅H₁₁, providedthat the following compound is excluded:


11. The compound of claim 10, wherein for the compound of formula I: R¹is CO₂R, wherein R is H or CO₂R forms a pharmaceutically acceptable saltor a pharmaceutically acceptable ester; A and B are C₁₋₅ alkyl, alkenyl,or alkynyl or C₃₋₅ allenyl group; C is

D is a C₃ alkyl, alkenyl, or alkynyl group; X is (CH₂)_(m) or(CH₂)_(m)O, wherein m is 1 or 2; and Y is a phenyl ring optionallysubstituted with halo, trihalomethyl, or a free or functionally modifiedhydroxy group; or X—Y is n-C₅H₁₁ or cyclohexyl; or X—Y is Y¹; wherein


12. The compound of claim 11, wherein the compound of formula I isselected group consisting of: